肝星状细胞中促纤维化和抗纤维化信号间的关键节点与新型药物靶标确证

TGF-β signaling plays a key role in the pathogenesis of liver fibrosis and hepatocarcinoma. However, there is still lack of an ideal molecule as a drug target. Our previous study found a key molecule CUGBP1 as a link between the profibrotic TGF-β and anti-fibrotic IFN-γ signaling pathways in hepatic satellite cells (HSCs). On the basis of this result, this study aims at establishing a novel approach to the recovery from liver fibrosis via targeting CUGBP1 and its interaction with the target genes. We will confirm the key molecule effect of CUGBP1 that controls some anti-fibrotic signals, and evaluate its relation to the progress of and recovery from the liver fibrosis. We will establish a series of assays for targeting CUGBP1 and its interaction with the target genes. Then, we will verify the drug target property by means of genetic approaches, inhibitors of various signal pathways, and current anti-fibrotic drugs. Based on these findings, we will search for a lead compound with its chemical and biological features and a potential drug candidate after structural optimization. Then, examination will be performed on the relation of the anti-CUGBP1 activity of the selected compound to the homeostasis of HSCs, as well as to the anti-liver fibrotic and anti-hepatocarcinoma effects. This study will lay the foundation for the new drug development against liver fibrosis and hepatocarcinoma.

TGF-β信号在肝纤维化及肝癌的发生发展过程中起关键作用，但其作为药物靶标却缺少合适的切入点。我们的前期研究发现了肝星状细胞中促纤维化TGF-β信号和抗纤维化IFN-γ信号之间的关键链接分子CUGBP1。本项目拟通过靶向抑制CUGBP1及其与靶基因的相互作用，增强内源性抗纤维化信号，确立恢复肝纤维化制衡的新方法。包括：确证CUGBP1具有调控多种抗纤维化信号的关键节点样作用，探讨其与肝纤维化进展与转归的关联；建立基于CUGBP1及其与靶基因相互作用的活性评价及多层次的药物筛选体系；借助遗传操纵法、各种信号通路抑制剂及现有抗纤维化药物等证实其药物靶标属性；在此基础上发现先导化合物、探讨其化学特征和作用特点，经结构优化获得潜在的候选药物；系统探讨选定的化合物靶向CUGBP1及其与靶基因的相互作用与恢复肝星状细胞稳态、抗肝纤维化和抗肝癌活性的相关性，为新型抗肝纤维化和抗肝癌药物的研制奠定基础。

肝纤维化的治疗目前尚无有效的方法，TGF-β信号在肝纤维化中起关键作用，但该信号功能广泛，其靶向药物研发面临挑战。我们另辟蹊径发现了“促纤维化”和“抗纤维化”信号间的关键节点分子CUGBP1，希望从该节点切入调控肝纤维化。本项目的研究内容主要包括：确证CUGBP1具有控制不同纤维化信号的关键节点样作用，探讨其与肝纤维化进展与转归的关联；证实其药物靶标属性；建立多层次活性评价体系；发现先导化合物；探讨化合物抗肝纤维化的药理学活性与机制等。.上述各项研究内容均已顺利完成：发现了CUGBP1调控的靶基因群，包括降解靶基因IFNG，通过EF1A1正调控靶基因RIF1的翻译等，证明了CUGBP1 在不同纤维化信号间的关键节点样作用；建立了针对CUGBP1 及其与靶基因相互作用的虚拟筛选、无细胞筛选、细胞筛选和动物模型等多层次活性评价体系；证实CUGBP1在肝纤维化患者中高表达并与纤维化的程度成正比，利用遗传操纵、小分子抑制剂等证实CUGBP1 的新型药物靶标属性；发现能结合CUGBP1并调控“CUGBP1-靶基因”相互作用的化合物27及经优化的841，以及化合物78及其衍生物等。.上述发现为肝纤维化的发生发展机理提供了新的解释，以促纤维化和抗纤维化信号间博弈的关键节点作为治疗的切入点和潜在药物靶标具有重要的科学意义。鉴于RNA结合蛋白通常被认为“不可成药”，本研究建立的活性评价体系还可为靶向RNA结合蛋白的药物发现提供重要参考，发现的活性化合物可为新型肝纤维化治疗药的研发奠定基础。.已发表并标注该项目资助的SCI论文31篇，其中STTT 3篇，APSB 和Nat Commun各2篇，Nucleic Acids Res、Redox Biol、EMBO Mol Med、Arthritis Rheumatol、Br J Pharmacol、JBC 各1篇等，申请发明专利2件。

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